The QMI section has an active and ongoing role in several collaborative projects involving the Center for Neuroscience and Regenerative Medicine (CNRM) and the Uniformed Services University (USU) that are part of a coordinated effort across institutions and agencies to rapidly advance TBI research. The role of QMI in these projects is centered on advanced acquisition, processing and analysis of MRI data especially diffusion MRI for the evaluation of brain outcomes in experimental models that have been carefully selected to better understand of particular aspects of TBI such as mild injury, diffuse axonal injury and dietary neuroprotective approaches. Below are categorized brief synopses of progress in the reporting period related to this research. Pre-clinical and ex-vivo imaging methodology advancements. A central foundation of QMI research is that the rigorous understanding and implementation of advanced quantitative imaging approaches is crucial for the effective application of imaging tools. The applied research objectives for detection of imaging abnormalities in TBI are approached by migrating the tools and practices from the QMI project Processing and Analysis of Quantitative Diffusion MRI Data along with pre-clinical and microscale MRI acquisition development to provide a powerful methodological framework for the investigation of TBI. During this reporting period, two studies and a review article were published demonstrating these efforts. 1. The first study was a comprehensive comparison of the effects of image quality and DWI sampling on outcome measures across multiple advanced diffusion MRI modeling approaches. The samples used in this study were uninjured ex-vivo mouse brains and the central findings outline the advantages and vulnerabilities of different diffusion MRI approaches. 2. The second completed study of this period was the generation of set of ferret brain MRI and DTI templates made possible in part by the correction and registration tools developed by QMI (i.e. DRBUDDI and DRTAMAS). Ex-vivo and in-vivo T2-weighted MRI and DTI map volumes from uninjured adult male ferrets (n=26 for in-vivo templates, n=8 for ex-vivo templates) as well as ROI masks for neuroanatomical regions of the ferret brain. 3. A review article was published to compile a comprehensive description of the many cellular alterations that evolve following brain injury and may influence diffusion MRI outcomes along with a encompassing description of higher-order and advanced diffusion MRI models that may be advantageous for the detection of these abnormalities. In addition to a literature review of the DTI studies of experimental TBI that have been performed to date, this review included a perspective of the potential utility that newer diffusion MRI tools (extending beyond DTI) may afford TBI research. Diffusion MRI of mild TBI in the ferret The ferret has been identified as a potentially important species for the study of TBI outcomes as it has a gyrencephalic cortical geometry and higher white matter volume than rodents. Additionally, it is one of the few species with these attributes with body dimensions to allow MRI experiments using specialized pre-clinical MRI scanners. During this reporting period a large and long standing collaborative project to evaluate the outcomes of mild focal TBI and blast injury in the ferret have reached a stage of analysis and completion. The main MRI findings from this work have begun to be published including a description of the acute T2 and diffusion MRI changes found in-vivo after controlled cortical impact (CCI). During this reporting period, the analysis and evaluation of longitudinal in-vivo and high-quality ex-vivo data from 22 adult male ferrets with CCI and 7 ferrets with blast injury compared with 9 uninjured ferrets has resulted in a number of observations about diffusion abnormalities following brain injury that have been presented in oral presentations and posters at conferences and are the source of findings for ongoing preparation of manuscripts on the findings. A new study in the ferret has also been initiated to develop and evaluate a new experimental model of closed head injury of rotation/acceleration and during this period the administrative, material and conceptual foundations of this research have been formed and development of non-diffusion MRI approaches is underway in collaboration with the CNRM imaging core, including quantitative susceptibility mapping, dynamic contrast imaging and arterial spin labeling. MRI evaluation of DHA treatment in mice A third TBI-related project is the evaluation of DHA deficiency and the effects of DHA treatment on imaging outcomes in the mouse brain in CNRM facilitated collaboration with a lab in the NIAAA. During the reporting period an animal protocol for QMI was written and submitted to perform some parts of the study at NIH. In addition, ex-vivo evaluation of a closed head injury model that will be used in this study was performed by statistical comparison between DTI markers and histological data. Another study was performed to identify diffusion markers of axonal injury in this model by the double-PFG method developed by a collaborating NICHD lab. MRI development work for procedures to be used in this study was also performed in collaboration with the USU MRI facility.